Benzothiazoline compounds

ABSTRACT

This invention relates to benzothiazoline derivatives of the formula [I] and salts thereof, which are useful for (i) treating cardiovascular diseases, and (ii) as the active ingredient of pharmaceutical compositions. Formula [I] follows: ##STR1## wherein R 1  is lower alkanoyl; 
     R 2  is one or more group(s) selected from hydrogen, lower alkyl, lower alkoxy, hydroxy, halogen, nitro, halogeno-lower alkyl and sulfamoyl; 
     R 3  is ##STR2## R 6  is hydrogen, alkyl, substituted alkyl, alkanoyl, substituted alkanoyl, alkenoyl, substituted alkenoyl or furylcarbonyl; 
     R 7  is hydrogen, hydroxy, phenyl-lower alkyl or banzoyl; 
     Z is strainght or branched alkylene containing 1 to 6 carbon atoms; 
     m is 0 or 1; n is 0 or 1; and p is 5.

SUMMARY OF THE INVENTION

This invention relates to benzothiazoline derivatives of the formula [I]and salts thereof, ##STR3## wherein

R¹ is lower alkanoyl;

R² is one or more group(s) selected from hydrogen, lower alkyl, loweralkoxy, hydroxy, halogen, nitro, halogenolower alkyl and sulfamoyl;

R³ is ##STR4## or --COR⁸ ;

R⁴ and R⁵, which may be same or different, each is hydrogen, loweralkyl, cyclohexyl or substituted lower alkyl wherein the substituent(s)is/are selected from the group consisting of hydroxy, phenyl, pyridyl,piperidyl or phenylcarbonyl, and said phenyl nucleus may beresubstituted by one or more groups selected from lower alkyl, hydroxy,halogen, lower alkoxy, nitro, cyano, acetamino and lower alkylamino;

R⁶ is hydrogen, alkyl containing 1 to 8 carbon atoms, alkanoylcontaining 2 to 8 carbon atoms, alkenoyl containing 2 to 8 carbon atomsor furylcarbonyl, each of which alkyl, alkanoyl and alkenoyl may besubstituted by one or more groups selected from hydroxy, phenyl andphenylcarbonyloxy, and said phenyl nucleus may be resubstituted by oneor more groups selected from lower alkyl, hydroxy, halogen, loweralkoxy, nitro, cyano, acetamino and lower-alkylamino;

R⁷ is hydrogen, hydroxy, phenyl-lower alkyl or benzoyl;

R⁸ is hydroxy, lower alkoxy, ##STR5##

Z is straight or branched alkylene containing 1 to 6 carbon atoms;

m is 0 or 1;

n is 0 or 1;

p is 4 or 5,

wherein the terms lower alkyl, lower alkoxy and lower alkanoyl refer togroups having 1 to 6 carbon atoms.

The same shall be applied hereinafter.

BACKGROUND OF THE INVENTION

The compounds of this invention are novel benzothiazoline derivativeswherein the substituent at 3-position on the benzothiazoline ring islower alkanoyl and that at 2-position is phenyl which is resubstitutedby ether group at any position. 2-Phenylbenzothiazoline derivatives werereported by H. Breuer et al. (U.S. Pat. No. 3,720,683), H. D. Cossey etal. (J. Chem. Soc., 1965, 954) and P. J. Palmer et al. (J. Med. Chem.,14, 248). The U.S. Pat. of Breuer et al. relates to2-phenylbenzothiazoline derivatives in which phenyl nucleus issubstituted by alkyl, etc. but not ether group, and the pharmacologicaleffects are for anti-inflammatory and anti-microbiral. Cossey et al. andPalmer et al. reported 2-phenylbenzothiazoline derivatives in whichphenyl nucleus is substituted by ether group, but the substituent of3-position is not lower alkanoyl but hydrogen, alkyl, benzyl, etc., andthe pharmacological effect is for anti-microbiral.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to benzothiazoline derivatives of the formula[I]. ##STR6##

The compounds of this invention are benzothiazoline derivatives whereinthe substituent at 3-position on the benzothiazoline ring is loweralkanoyl and that at 2-position is phenyl which is resubstituted byether group at any position. The compounds of this invention are notonly new in chemical structure but also found useful for treatment ofcardiovascular diseases and such effect on cardiovascular diseases hasnot been found in the known benzothiazoline derivatives. Cardiovasculardiseases are angina cordis, arrhythmia, thrombosis, etc., and β-blocker,inhibitor of platelet aggregation, calcium antagonist, etc. are used astherapeutic agent. From the pharmacological tests, it is proved that thecompounds of this invention possess a superior platelet anti-aggregationeffect and calcium antagonization, so they are useful for cardiovasculardiseases. Processes for preparing the compounds of this invention aresummarized as follows. The reaction of the compound of the formula [II]with the compound of the formula [III], ##STR7##

wherein X is halogen (the same shall be applied hereinafter), or thereaction reversed the above reaction order, i.e., the reaction of thecompound of the formula [IV] with the amine derivative, ##STR8## wherein

Y is halogen, carboxy or formyl, and Y and --OH may be jointed to formepoxy ring;

Amine derivative is ##STR9##

q is 0 or 1,

the same shall be applied hereinafter. The processes are explained indetail as follows. The reaction of the hydroxy derivative of the formula[II] with the halide of the formula [III] needs no specific conditions,and known methods which are generally used for a reaction of hydroxyderivative with halide can be employed, but preferably the reaction iscarried out in organic solvent (for example, dimethylformamide) in thepresence of base (for example, NaH). The reaction of the compound of theformula [IV] with amine derivative is divided into the following (a)-(d)reactions. ##STR10## Specific conditions are unnecessary for theabove-mentioned reactions. Methods which are generally used for areaction of amine derivative with halide, carboxylic acid derivative,aldehyde derivative or epoxy derivative can be employed.

The compounds of this invention can be converted to acid salts. Saidsalts are obtained by general methods using inorganic acids or organicacids. Examples of pharmaceutically acceptable salts of the compoundsare hydrochloride salt, sulfuric acid salt, phosphoric acid salt, lacticacid salt, maleic acid salt, fumaric acid salt, methanesulfonic acidsalt, p-toluenesulfonic acid salt, oxalic acid salt, etc.

The compounds of the formula [I] have stereoisomers because of theexistence of one or more asymmetric carbon atoms, and these isomers areincluded in this invention.

Examples are shown below, and the compounds of this invention are listedin Table I-IX.

The assignments of the NMR spectra in Table X are made according to thenumbers of the formula [IX]. ##STR11## But, protons (aromatic), not beassigned, are named as aromatic H (Ar--H). Proton of --OCH₃ group isassigned as --OCHHD 3(P) when the group is attached to C₂ '-C₆ 'position of the formula [IX], and assigned as --OCHHD 3(A) when thegroup is attached to the phenyl group which is the substituent of aminemoeity of the side chain.

EXAMPLE 13-Acetyl-2-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]benzothiazolinehydrochloride (Compound No. 86)

1.31 g of 3-acetyl-2-[2-(2,3-epoxypropoxy)phenyl]benzothiazoline and4.21 ml of t-butylamine are dissolved in 10 ml of ethanol and thesolution is refluxed for 1 hour. After cooling, 2 ml of 2N HCl/ethylacetate is added to the reaction mixture and the solution isconcentrated in vacuo. To the residue ether is added to producecrystals. Crystals are collected by filtration to give 1.3 g (81%) ofthe titled compound.

Physical data are shown in Table VII.

The compounds shown in Table VII are prepared by the similar methoddescrived above using corresponding amine derivatives.

EXAMPLE 23-Acetyl-2-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]benzothiazolinehydrochloride (Compound No. 86)

1.64 g of 3-acetyl-2-[2-(2,3-epoxypropoxy)phenyl]benzothiazoline, 1.82 gof 3-acetyl-2-[2-(3-chloro-2-hydroxypropoxy)phenyl]benzothiazoline and10 ml of t-butylamine are dissolved in 30 ml of ethanol and the solutionis refluxed for 3 hours. The solution is concentrated in vacuo, and theresidue is dissolved in ethyl acetate. The solution is washed withsaturated sodium chloride solution and dried over anhydrous magnesiumsulfate. To this solution 2N HCl/ether is added to produce crystals.Crystals are filtered to give 3.5 g (80%) of the titled compound.

The physical constant of the crystals is the same of the compoundobtained in Example 1.

EXAMPLE 3 3-Acetyl-2-[2-(3-dimethylaminopropoxy)phenyl]benzothiazoline(Compound No. 7)

To the suspension of 0.26 g of sodium hydride in anhydrous DMF, thesoution of 1.36 g of 3-acetyl-2-(2-hydroxyphenyl)-benzothiazoline in 5ml of anhydrous DMF is added dropwise under nitrogen atmosphere at roomtemperature. After the addition, the reaction mixture is stirred for 20minutes at room temperature. To the reaction mixture, the solution of0.61 g of 3-dimethylaminopropyl chloride in 10 ml of anhydrous DMF isadded. The reaction mixture is stirred for 2 hours at 80° C., and washedwith n-hexane after cooling and poured into ice-water. The separated oilis extracted with ethyl acetate. The organic layer is washed withN--NaOH solution, water and saturated sodium chloride solution in theorder named and dried over anhydrous magnesium sulfate. Ethy acetate isremoved off in vacuo to give 1.0 g (56%) of the titled compound.

Physical data are shown in Table I.

The compounds shown in Table I, II and III are prepared by the similarmethod described above using corresponding benzothiazoline derivativesand substituted aminoalkyl halides.

EXAMPLE 4 3-Acetyl-2-[2-(3-aminopropoxy)phenyl]benzothiazolinehydrochloride (Compound No. 1)

By substituting 0.83 g of 3-aminopropyl bromide for 3-dimetylaminopropylchloride in the procedure of Example 3, 1.2 g of the titled compound isobtained.

Physical data are shown in Table I.

EXAMPLE 5 3-Acetyl-2-[2-(3-diethylaminopropoxy)phenyl]benzothiazolinehydrochloride (Compound No. 10)

To the solution of 3.48 g of3-acetyl-2-[2-(3-chloropropoxy)-phenyl]benzothiazoline in 20 ml ofethanol, 10.3 ml of diethylamine is added and the mixture is refluxedfor 2 hours. After removal of ethanol and excess amount of diethylaminein vacuo, ethyl acetate and water are added to the residue. The organiclayer is extracted with N-hydrochloric acid, the acidic layer isalkalinized with N-sodium hydroxide solution and extracted with ethylacetate. The organic layer is washed with saturated sodium chloridesolution and dried over anhydrous magnesium sulfate. The solvent isremoved off in vacuo and the resulting oil is dissolved in methanol. Tothe solution hydrochloric acid in ethyl acetate is added to give 3.4 g(80%) of the titled compound.

Physical data are shown in Table I.

The compounds shown in Table I, II, III and VIII are prepared by thesimilar method described above using corresponding benzothiazolinederivatives and amine derivatives.

EXAMPLE 6 3-Acetyl-2-[2-(3-methylaminopropoxy)phenyl]benzothiazolinefumarate (Compound No. 2)

To the solution of 6.55 g of3-acetyl-2-[2-(3-oxopropoxy)-phenyl]benzothiazoline in 100 ml ofmethanol, 8.10 g of methylamine hydrochloride and 10.0 g of molecularsieves(3A), smashed into fine pieces, are added. To the suspension 1.26g of sodium cyano borohydride is added and the mixture is stirred for 1hour at room temperature. 2N-Hydrochloric acid is added to the reactionmixture and methanol is removed off in vacuo. The aqueous layer iswashed with ethyl acetate and alkalinized with 2N-sodium hydroxidesolution and extracted with ethyl acetate. The organic layer is washedwith saturated sodium chloride solution and dried over anhydrousmagnesium sulfate. The solvent is removed off in vacuo and the resultingoil is dissolved in methanol. To the solution fumaric acid and ethylacetate are added to give 4.9 g (65%) of the titled compound.

Physical data are shown in Table I.

EXAMPLE 73-Acetyl-2-[2-[5-(N-cyclohexyl-N-methlamino)pentyloxy]-5-methoxyphenyl]benzothiazolinefumarate (Compound No. 21)

By substituting 4.50 g of3-acetyl-2-[2-(5-bromopentyloxy)-5-methoxyphenyl]benzothiazoline for3-acetyl-2-[2-(3-chloropropoxy)phenyl]benzothiazoline and 3.40 g ofN-methylcyclohexylamine for diethylamine in the procedure of Example 5,4.2 g (70%) of the titled compound is obtained.

Physical data are shown in Table I.

The compounds shown in Table I are prepared by the similar methoddescribed above using corresponding benzothiazoline derivatives andamine derivatives.

EXAMPLE 83-Acetyl-2-[3-[3-(N-cyclohexyl-N-methylamino)propoxy]-4-hydroxyphenyl]benzothiazolinefumarate (Compound No. 37)

3.64 g of3-acetyl-2-[3-(3-chloropropoxy)-4-hydroxyphenyl]-benzothiazoline and3.40 g of N-methylcyclohexylamine are stirred at 100° C. for 1 hour.After cooling to room temperature, the reaction mixture is dissolved in50 ml of chloroform, the solution is washed with N-hydrochloric acid,N-sodium hydroxide solution and saturated sodium chloride solution inthe named order and dried over anhydrous magnesium sulfate. Chloroformis removed off in vacuo and the residue is purified by silica gel columnchromatography. The oily product is dissolved in 20 ml of ethyl acetate.To the solution 0.71 g of fumaric acid in 3 ml of methanol is added togive 2.7 g (50%) of the titled compound.

Physical data are shown in Table II.

The compounds shown in Table II and III are prepared by the similarmethod described above using corresponding benzothiazoline derivativesand amine derivatives.

EXAMPLE 93-Acetyl-2-[2-[2-[4-(3,4-dimethoxyphenetyl)-1-piperazinyl]ethoxy]-phenyl]benzothiazolinedimaleate (Compound No. 57)

3.34 g of 3-acetyl-2-[2-(2-chloroethoxy)phenyl]benzothiazoline and 5.01g of 1-(3,4-dimethoxyphenetyl)piperazine are stirred at 110° C. for 1hour. After cooling to room temperature, the reaction mixture isdissolved in 50 ml of chloroform, the solution is washed withN-hydrochloric acid, N-sodium hydroxide solution and saturated sodiumchloride solution in the named order and dried over anhydrous magnesiumsulfate. Chloroform is removed off in vacuo and the resulting oil isdissolved in 50 ml of ethyl acetate. To the solution 2.32 g of maleicacid in 30 ml of ethyl acetate is added to give 6.24 g (80%) of thetitled compound.

Physical data are shown in Table IV.

The compounds shown in Table I, IV, V, VI and VIII are prepared by thesimilar method described above using corresponding benzothiazolinederivatives and amine derivatives.

EXAMPLE 103-Acetyl-2-[2-[3-(ethoxycarbonyl)propoxy]phenyl]benzothiazoline(Compound No. 97)

To the suspension of 1.59 g of sodium hydride in 30 ml of anhydrous DMF,the solution of 8.13 g of 3-acetyl-2-(2-hydroxyphenyl)benzothiazoline in30 ml of anhydrous DMF is added dropwise under nitrogen atmosphere atroom temperature. After the addition, the reaction mixture is stirredfor 20 minutes at room temperature. To the reaction mixture, thesolution of 4.95 g of ethyl 4-chlorobutyrate in 15 ml of anhydrous DMFis added and stirred for 5 hours at 70° C. After cooling to roomtemperature the reaction mixture is poured into ice-water and extractedwith ethyl acetate.

The organic layer is washed with N-potassium hydroxide solution, water,N-hydrochloric acid and saturated sodium chloride solution in the namedorder and dried over anhydrous magnesium sulfate. The solvent is removedoff and the resulting oil is purified by silica gel columnchromatography to give 8.67 g (75%) of the titled compound.

Physical data are shown in Table IX.

EXAMPLE 11 3-Acetyl-2-[2-[3-(carboxy)propoxy]phenyl]benzothiazoline(Compound No. 96)

To the solution of 7.71 g of3-acetyl-2-[2-[3-(ethoxycarbonyl)-propoxy]phenyl]benzothiazoline in 50ml of methanol, 2N-sodium hydroxide solution is added and the reactionmixture is stirred for 2 hours at room temperature. Methanol is removedoff in vacuo. The residue is acidified with 2N-hydrochloric acid to give5.72 g (80%) of the titled compound.

Physical data are shown in Table IX.

EXAMPLE 123-Acetyl-2-[2-[3-(morpholinocarbonyl)propoxy]phenyl]benzothiazoline(Compound No. 100)

To the solution of 1.79 g of3-acetyl-2-[2-[3-(carboxy)-propoxy]phenyl]benzothiazoline and 0.51 g oftriethylamine in 20 ml of anhydrous methylene chloride, 0.68 g ofisobutyl chloroformate is added dropwise while stirring at -13° C. andstirred additional 10 minutes at the same temperature. To the solution0.44 g of morpholine in 5 ml of methylene chloride is added dropwise.

After the addition, the reaction mixture is stirred for 1 hour underice-water cooling and for 1 hour at room temperature. The reactionmixture is washed with 5% citric acid solution, water, N-potassiumhydroxide solution and saturated sodium chloride solution in the namedoder and dried over anhydrous magnesium sulfate. The solvent is removedoff in vacuo to give 1.60 g (75%) of the titled compound.

Physical data are shown in Table IX.

The compounds shown in Table IX are prepared by the similar methoddescribed above using corresponding amine derivatives.

                                      TABLE I                                     __________________________________________________________________________     ##STR12##                                                                                                      Method                                                                        of prepn.                                                                              mp (°C.)                    Compd.                            (Examp.                                                                            Yield                                                                             (Recrystn.                         No.  R.sup.2                                                                            R.sup.4 R.sup.5       r No.) (%) solvent)   IR(KBr,                 __________________________________________________________________________                                                          cm.sup.-1)               1*.sup.1                                                                          H    H       H             3 4    65  106-109(dec.)                                                                            3400, 1660, 1466,                                                             1382, 1232, 748          2*.sup.2                                                                          H    H       CH.sub.3      3 6    65  111-113    3420, 1674, 1458,                                                             1370, 724, 616           3*.sup.1                                                                          H    H       C(CH.sub.3).sub.3                                                                           4 5    75  193-195    3500, 3430, 2950,                                                             2770, 1667, 1585,                                                             1455, 1371, 1320,                                                             1266, 1221, 1095,                                                             741                        4*.sup.1                                                                        H    H                                                                                      ##STR13##    3 5    75  235.5-238.0 (dec.)                                                                       3020, 2940, 1678,                                                             1598, 1488, 1462                                                              1376, 1244, 1226,                                                             1098, 744                  5*.sup.1                                                                        H    H                                                                                      ##STR14##    3 5    70  165-169    3420, 2940, 1676,                                                             1514, 1462, 1378,                                                             1324, 1262, 1250,                                                             1288, 1022, 746            6*.sup.1                                                                        H    CH.sub.3                                                                              CH.sub.3      2 3    80  209-210    3430, 1670, 1460,                                                  (MeOHAcOEt)                                                                              1387, 1354, 1325,                                                             1272, 1245, 1230,                                                             1170, 1103, 1050,                                                             1022, 930, 750           7   H    CH.sub.3                                                                              CH.sub.3      3 3    56  92.5-94.5  1678, 1600, 1466,                                                  ((Me.sub.2 CH).sub.2 O                                                                   1376, 1312, 1274,                                                  hexane)    1246, 1218, 1006,                                                             746                        8*.sup.1                                                                        H    CH.sub.3                                                                               ##STR15##    3 5    75  130-142 (MeOHAcOEt)                                                                      3400, 2930, 2910,                                                             1672, 1464, 1380,                                                             1322, 1272, 1242,                                                             1224, 750                  9*.sup.3                                                                        H    CH.sub.3                                                                              CH.sub.2 Ph   3 5    80  159-162    3450, 1676, 1580,                                                             1490, 1466, 1380,                                                             750, 702                10*.sup.1                                                                          H    CH.sub.2 CH.sub.3                                                                     CH.sub.2 CH.sub.3                                                                           3 5    80  154-156    3480, 3420, 2930,                                                  (MeOHAcOEt)                                                                              1676, 1462, 1378,                                                             1320, 1270, 1240,                                                             1224, 1098, 752         11*.sup.1                                                                          H    CH.sub.2 CH.sub.3                                                                     CH.sub. 2 CH.sub.3                                                                          4 5    80  amorph.    3420, 1665, 1465,                                                             1380, 1324, 1270,                                                             1230, 748               12*.sup.1                                                                          H                                                                                   ##STR16##                                                                             ##STR17##    3 5    65  amorph.    2940, 2870, 1684,                                                             1468, 1380, 750           13*.sup.1                                                                        H    CH.sub.2 CH.sub.2 OH                                                                  CH.sub.2 CH.sub.2 OH                                                                        3 9    60  145-149    3320, 1666, 1466,                                                             1380, 1314, 1236,                                                             748                     14*.sup.1                                                                          3-OCH.sub.3                                                                        CH.sub.3                                                                              CH.sub.3      3 3    70  221-222    3410, 1665, 1580,                                                  (MeOH)     1465, 1375, 1343,                                                             1270, 1232, 1060,                                                             1030, 753, 740          15*.sup.1                                                                          3-OCH.sub.3                                                                        CH.sub.3                                                                              CH.sub.3      4 5    65  199-200    3420, 2930, 1675,                                                             1575, 1460, 1375,                                                             1268, 753, 740            16*.sup.3                                                                        3-OCH.sub.3                                                                        CH.sub.3                                                                               ##STR18##    3 5    70  amorph.    3400, 2930, 1710,                                                             1665, 1575, 1460,                                                             1370, 1268, 1055,                                                             745                       17*.sup.1                                                                        3-OCH.sub.3                                                                        CH.sub.3                                                                               ##STR19##    4 5    60  197-198    3550, 3460, 2950,                                                             1675, 1660, 1482,                                                             1466, 1380, 1272,                                                             1055, 775, 750            18*.sup.3                                                                        5-OCH.sub.3                                                                        CH.sub.3                                                                              CH.sub.3      3 3    73  165.5-166  3430, 1672, 1580,                                                  (MeOH)     1492, 1465, 1373,                                                             1207, 1053, 870,                                                              749                       19*.sup.4                                                                        5-OCH.sub.3                                                                        CH.sub.3                                                                               ##STR20##    3 5    80  191.5-192 (dec.) (CH.sub.3                                                    CNMeOH)    3420, 3180, 2860,                                                             1769, 1670, 1498,                                                             1460, 1380, 1368,                                                             1300, 1280, 1209,                                                             1060, 750, 715            20*.sup.4                                                                        5-OCH.sub.3                                                                        CH.sub.3                                                                               ##STR21##    4 5    60  147-148 (CH.sub.3 CN)                                                                    3420, 1670, 1493,                                                             1463, 1372, 1275,                                                             1240, 1208, 1037,                                                             743, 720                  21*.sup.2                                                                        5-OCH.sub.3                                                                        CH.sub.3                                                                               ##STR22##    5 7    70  155.5-157.5                                                                              3420, 2930, 1670,                                                             1466, 1380, 1275,                                                             1207                      22*.sup.4                                                                        5-OCH.sub.3                                                                        CH.sub.3                                                                               ##STR23##    6 7    55  135-137    3440, 1675, 1493,                                                             1465, 1380, 1280,                                                             1210, 1040, 750,                                                              720, 700                  23*.sup.1                                                                        5-OCH.sub.3                                                                        CH.sub.3                                                                               ##STR24##    4 9    80  amorph.    3424, 1664, 1493,                                                             1463, 1377, 1321,                                                             1272, 1262, 1236,                                                             1208, 1155, 1028                                                              748                       24*.sup.1                                                                        5-OCH.sub.3                                                                         ##STR25##                                                                            CH.sub.2 CH.sub.2 OH                                                                        4 9    70  amorph.    3336, 1664, 1493,                                                             1464, 1397, 1274,                                                             1208, 1036, 748           25*.sup.1                                                                        5-OCH.sub.3                                                                         ##STR26##                                                                             ##STR27##    4 9    75  amorph.    3424, 1668, 1510,                                                             1496, 1466, 1272,                                                             1262, 1237, 1208,                                                             1025, 750                  26*.sup.1                                                                       5-Cl CH.sub.3                                                                              CH.sub.3      3 3    70  193-195.5  3420, 1678, 1466,                                                  ((Me.sub.2 CH).sub.2 OEt.sub.2                                                O)         1376, 1226, 1110,                                                             1035, 764                  27*.sup.1                                                                       3-NO.sub.2                                                                         CH.sub.3                                                                               ##STR28##    3 5    70  103-106    3420, 1668,                                                                   1598,1528, 1464,                                                              1376,1348, 1319,                                                              1270,1225, 742             28*.sup.2                                                                       5-NO.sub.2                                                                         CH.sub.3                                                                              CH.sub.3      3 3    65  159-160 (dec.)                                                                           3420, 1670, 1610                                                   (MeOHCH.sub.3 CN                                                                         1591, 1515, 1463,                                                             1379, 1340, 1268,                                                             1225, 1078, 1032,                                                             980, 745                   29*.sup.2                                                                       5-NO.sub.2                                                                         CH.sub.3                                                                               ##STR29##    3 5    55  168-169 (dec.)(MeOHCH.sub.3                                                   CN)        3460, 1693,                                                                   1670,1588, 1512,                                                              1461,1375, 1336,                                                              1265,1212, 1074,                                                              741                        30*.sup.2                                                                       5-NO.sub.2                                                                         CH.sub.3                                                                               ##STR30##    4 5    60  176.5-178 (dec.)(MeOHCH.sub.3                                                 CN)        3420, 1695,                                                                   1591,1510, 1465,                                                              1379,1341, 1267,                                                              1226,1079, 755             31*.sup.2                                                                       5-NO.sub.2                                                                         CH.sub.3                                                                               ##STR31##    5 7    70  172-174 (dec.)(MeOHCH.sub.3                                                   CN)        3430, 1710,                                                                   1675,1591, 1511,                                                              1467,1380, 1336,                                                              1265,1230, 1078,                                                              982,747                    32*.sup.2                                                                       5-NO.sub.2                                                                         CH.sub.3                                                                               ##STR32##    6 7    70  178-180 (dec.)(MeOHCH.sub.3                                                   CN)        3430, 1715,                                                                   1679,1591, 1511,                                                              1461,1377, 1335,                                                              1268,1227, 1077,                                                              982,749                    33*.sup.5                                                                       5-NO.sub.2                                                                         H                                                                                      ##STR33##    3 9    55  83-85(AcOEt)                                                                             3400, 3290,                                                                   1678,1612, 1592,                                                              1580,1522, 1466,                                                              1348,1338, 1268,                                                              1080,748                   34*.sup.2                                                                       3OCH.sub.35-NO.sub.2                                                               CH.sub.3                                                                               ##STR34##    3 5    65  157-159(MeOHCH.sub.3 CN)                                                                 3420, 1705,                                                                   1677,1570, 1530,                                                              1463,1370, 1340,                                                              1294,1273, 1213,                                                              11941162, 1062,                                                               981,63,                 __________________________________________________________________________                                                          738                      *.sup.1 Hydrochloride                                                         *.sup.2 Fumarate                                                              *.sup.3 Maleate                                                               *.sup.4 Oxalate                                                               *.sup.5 Monohydrate                                                      

                                      TABLE II                                    __________________________________________________________________________     ##STR35##                                                                                         Method                                                                        of         mp(°C.)                                Compd.               prepn. Yield                                                                             (Recrystn.                                    No.  R.sup.2                                                                            R.sup.4                                                                           R.sup.5                                                                            r (Examp. No.)                                                                         (%) solvent)                                                                              IR(KBr, cm.sup.-1)                    __________________________________________________________________________    35*.sup.1                                                                          H    CH.sub.3                                                                          CH.sub.3                                                                           3 3      70  162-164 3420, 1716, 1680, 1606, 1586,                                                 1463, 1381, 1306, 1288, 954           36   4-OH CH.sub.3                                                                          CH.sub.3                                                                           3 8      30  oil     3340, 1675, 1585, 1510, 1480,                                                 1430, 1300, 1270, 1141, 750                                                   (neat)                                37*.sup.1                                                                          4-OH CH.sub.3                                                                           ##STR36##                                                                         3 8      50  130-133 (dec.)                                                                        3400, 1670, 1575, 1510, 1462,                                                 1430, 1375, 1340, 1320, 1272,                                                 1230, 1208, 985, 745                    38*.sup.2                                                                        4-OCH.sub.3                                                                        CH.sub.3                                                                           ##STR37##                                                                         4 5      85  amorph. 3400, 1660, 1512, 1460, 1380,                                                 1340, 1255, 1135, 1020, 750             39*.sup.2                                                                        4-NO.sub.2                                                                         CH.sub.3                                                                           ##STR38##                                                                         3 5      70  115-117 3420, 1662, 1606, 1513, 1464,                                                 1375, 1343, 1314, 1272, 745             40*.sup.2                                                                        6-NO.sub.2                                                                         CH.sub.3                                                                           ##STR39##                                                                         3 5      65  69-73   3430, 1665, 1610, 1580, 1510,                                                 1468, 1378, 1318, 1290, 1226,         __________________________________________________________________________                                            748                                    *.sup.1 Fumarate                                                              *.sup.2 Hydrochloride                                                    

                                      TABLE III                                   __________________________________________________________________________     ##STR40##                                                                                            Method                                                                        of         mp(°C.)                             Compd.                  prepn. Yield                                                                             (Recrystn.                                 No. R.sup.2                                                                            R.sup.4                                                                             R.sup.5                                                                              r (Examp. No.)                                                                         (%) solvent)                                                                            IR(KBr, cm.sup.-1)                   __________________________________________________________________________    41*.sup.1                                                                         H    CH.sub.3                                                                            CH.sub.3                                                                             2 3      80  amorph.                                                                             3410, 1664, 1510, 1464, 1378,                                                 1234, 748                            42*.sup.1                                                                         H    CH.sub.3                                                                            CH.sub.3                                                                             3 3      75  oil   3400, 1660, 1610, 1580, 1460,                                                 1380, 1230, 1174, 750                                                         (neat)                               43*.sup.1                                                                         H    CH.sub.3                                                                            CH.sub.3                                                                             4 5      80  amorph.                                                                             3420, 2940, 1666, 1510, 1464,                                                 1376, 1244, 1174, 748                  44*.sup.1                                                                       H    CH.sub.3                                                                             ##STR41##                                                                           3 5      75  amorph.                                                                             3420, 2940, 1684, 1510, 1462,                                                 1376, 1326, 1268, 1244, 1230,                                                 1174, 748                              45*.sup.1                                                                       H    CH.sub.3                                                                             ##STR42##                                                                           4 5      75  amorph.                                                                             3420, 2940, 1666, 1510, 1464,                                                 1376, 1328, 1270, 1244, 1174,                                                 748                                    46*.sup.1                                                                       H    CH.sub.2 CH.sub.3                                                                   CH.sub.2 CH.sub.3                                                                    3 5      75  amorph.                                                                             3420, 2930, 1662, 1506, 1460,                                                 1374, 1324, 1266, 1238, 1172,                                                 748                                    47 .sup.                                                                        3-OH CH.sub.3                                                                             ##STR43##                                                                           3 8      40  oil   3330, 1666, 1575, 1502, 1461,                                                 1376, 1340, 1270, 1216, 1121,                                                 1025, 745 (neat)                       48*.sup.1                                                                       3-OCH.sub.3                                                                        CH.sub.3                                                                            CH.sub.3                                                                             3 3      80  amorph.                                                                             3420, 1662, 1510, 1460, 1375,                                                 1335, 1256, 1230, 1132, 1025,                                                 746                                  49*.sup.1                                                                         3-OCH.sub.3                                                                        CH.sub.3                                                                            CH.sub.3                                                                             4 5      70  amorph.                                                                             3420, 1665, 1510, 1462, 1375,                                                 1255, 1230, 1132, 1025, 750            50*.sup.1                                                                       3-OCH.sub.3                                                                        CH.sub.3                                                                             ##STR44##                                                                           3 5      75  amorph.                                                                             3420, 1666, 1512, 1465, 1378,                                                 1255, 1230, 1135, 1027, 750            51*.sup.1                                                                       3-OCH.sub.3                                                                        CH.sub.3                                                                             ##STR45##                                                                           4 5      70  amorph.                                                                             3400, 1663, 1510, 1460, 1378,                                                 1255, 1132, 1025, 746                  52*.sup.1                                                                       3-NO.sub.2                                                                         CH.sub.3                                                                             ##STR46##                                                                           3 5      75  amorph.                                                                             3420, 1665, 1618, 1530, 1463,                                                 1376, 1350, 1320, 1270, 1081,                                                 1027, 749                              53*.sup.1                                                                       3-OCH.sub.3                                                                        CH.sub.3                                                                            CH.sub.3                                                                             3 5      65  amorph.                                                                             3410, 2940, 1656, 1582, 1452,            5-OCH.sub.3                          1412, 1368, 1318, 1220, 1112,                                                 740                                    54*.sup.1                                                                       3-OCH.sub.3 5-OCH.sub.3                                                            CH.sub.3                                                                             ##STR47##                                                                           3 5      60  amorph.                                                                             3440, 2950, 1664, 1588, 1462,                                                 1420, 1380, 1338, 1236, 1124,                                                 752                                    55*.sup.1                                                                       3-OCH.sub.3 5-OCH.sub.3                                                            CH.sub.3                                                                             ##STR48##                                                                           4 5      75  amorph.                                                                             3420, 2932, 1664, 1589, 1458,                                                 1419, 1379, 1327, 1271, 1229,                                                 1122                                 __________________________________________________________________________     *.sup.1 Hydrochloride                                                    

                                      TABLE IV                                    __________________________________________________________________________     ##STR49##                                                                                                   Method                                                                        of         mp(°C.)                      Compd.                         prepn. Yield                                                                             (Recrystn.                          No.  R.sup.2                                                                            R.sup.6            r (Examp. No.)                                                                         (%) solvent)  IR(KBr,                   __________________________________________________________________________                                                        cm.sup.-1)                56*.sup.1                                                                          H    CH.sub.3           3 3      65  213-215   3400, 1664, 1460,                                                             1376,                                                                         1322, 1272, 1226,                                                             746                         57*.sup.2                                                                        H                                                                                   ##STR50##         2 9      80  181-182 (dec.) (MeOHCH.sub.3                                                  CN)       3430, 1683, 1615,                                                             1573, 1513, 1460,                                                             1375, 1352,  1319,                                                            1259, 1222, 1095,                                                             1022, 860, 755              58*.sup.2                                                                        H                                                                                   ##STR51##         3 9      70  172-173 (dec.) (MeOHCH.sub.3                                                  CN)       3430, 1687, 1619,                                                             1570, 1515, 1460,                                                             1378, 1352, 1321,                                                             1260, 1238, 1225,                                                             1098, 1024, 864, 755,                                                         43                          59*.sup.3                                                                        H                                                                                   ##STR52##         2 9      60  144-146 (dec.) (MeOHCH.sub.3                                                  CN)       3420, 1705, 1682,                                                             1651, 1586, 1511,                                                             1459, 1374, 1263,                                                             1223, 1152, 1022,                                                             751                         60*.sup.3                                                                        H                                                                                   ##STR53##         3 9      75  149-151 (dec.) (CH.sub.3                                                                3420, 1712, 1679,                                                             1647, 1590, 1513,                                                             1460, 1375, 1262,                                                             1227, 1155, 1023,                                                             975, 750                    61*.sup.4                                                                        H                                                                                   ##STR54##         3 9      85  131-132 (dec.) (MeOHEt.sub.2                                                            3420, 1670, 1640,                                                             1585, 1512, 1459,                                                             1374, 1260, 1138,                                                             1022, 740                   62*.sup.2                                                                        5-OCH.sub.3                                                                         ##STR55##         3 9      60  181-182 (dec.) (MeOHCH.sub.3                                                  CN)       3430, 1671, 1618,                                                             1572, 1492, 1462,                                                             1377, 1353, 1322,                                                             1260, 1236, 1207,                                                             1155, 1099, 1025,                                                             862, 745                    63*.sup.5                                                                        5-OCH.sub.3                                                                         ##STR56##         4 9      65  197.5-198.5  (MeOHCH.sub.3                                                              3420, 1708, 1668,                                                             1575, 1495, 1461,                                                             1373, 1295, 1267,                                                             1233, 1205, 1152,                                                             1022, 973, 743              64*.sup.2                                                                        5-OCH.sub.3                                                                         ##STR57##         5 9      70  195.5-197.5 (dec.)                                                                      3440, 1664, 1580,                                                             1500, 1466, 1381,                                                             1208, 1023, 865             65*.sup.2                                                                        5-OCH.sub.3                                                                         ##STR58##         6 9      80  188-189 (MeOHCH.sub.3 CN)                                                               3430, 1670, 1618,                                                             1570, 1465, 1380,                                                             1354, 1260, 1240,                                                             1210, 1027, 865             66*.sup.2                                                                        5-OCH.sub.3                                                                        CH.sub.2 CH.sub.2 CH                                                                             4 9      80  186-187 (dec.) (MeOHCH.sub.3                                                  CN)       3480, 1700, 1672,                                                             1620, 1575, 1490,                                                             1468, 1380, 1359,                                                             1276, 1210, 1070,                                                             865, 746                    67*.sup.1                                                                        5-OCH.sub.3                                                                         ##STR59##         4 9      80  239-240 (dec.                                                                           3420, 1674, 1588,                                                             1500, 1460, 1420,                                                             1376, 1232, 1212,                                                             1120, 1040, 758             68*.sup.2                                                                        5-OCH.sub.3                                                                         ##STR60##         4 9      80  175-177  (EtOHCH.sub.3 CN)                                                              3430, 1664, 1571,                                                             1492, 1465, 1379,                                                             1360, 1277, 1208,                                                             1102, 1062, 864             69*.sup.5                                                                        5-OCH.sub.3                                                                         ##STR61##         4 9      70  170-173   3440, 1491, 1465,                                                             1379, 1274, 1209,                                                             752                         70*.sup.2                                                                        5-OCH.sub.3                                                                         ##STR62##         4 9      75  181-182.5 (dec.) (MeOHCH.sub.3                                                CN)       3450, 1710, 1672,                                                             1580,  1466, 1378,                                                            1355, 1330, 1210,                                                             1123, 862, 746            71*.sup.3                                                                          5-OCH.sub.3                                                                         ##STR63##         3 9      65  130-131 (dec.) (AcOEt)                                                                  3420, 1701, 1660,                                                             1641, 1590, 1515,                                                             1499, 1463, 1372,                                                             1272, 1260, 1231,                                                             1207, 1140, 1023,                                                             980, 750                    72*.sup.6                                                                        5-OCH.sub.3                                                                         ##STR64##         3 9      70  175-176 (dec.) (MeOHCH.sub.3                                                  CN)       3430, 1641, 1580,                                                             1509, 1462, 1373,                                                             1260, 1207, 1136,                                                             1022, 975, 863, 745       73*.sup.2                                                                          5-NO.sub.2                                                                          (CH.sub.2).sub.7 CH.sub.3                                                                       3 9      75  176.5-177.5                                                                             3420, 1676, 1610,                                                             1580,                                                               (MeOHCH.sub.3 CN)                                                                       1510, 1468, 1380,                                                             1342,                                                                         1272, 1080, 865, 748        74*.sup.2                                                                        5-NO.sub.2                                                                          ##STR65##         3 9      90  156.5-1158 (dec.) (MeOHCH.sub.3                                               CN)       3420, 1660, 1573,                                                             1508, 1461, 1378,                                                             1262, 1020, 860, 741,                                                         710                         75*.sup.7                                                                        5-NO.sub.2                                                                         CO(CH.sub.2).sub.6 CH.sub.3                                                                      3 9      70  90-92.5   3450, 1650, 1590,                                                             1466,                                                               (CHCl.sub.3Et.sub.2 O)                                                                  1340, 1270, 748, 712        76*.sup.2                                                                        5-NO.sub.2                                                                          ##STR66##         3 9      75  144-145 (dec.)                                                                          3410, 1661, 1572,                                                             1508, 1462, 1378,                                                             1337, 1267, 1225,                                                             1074, 1011, 860, 741        77*.sup.2                                                                        5-NO.sub.2                                                                          ##STR67##         3 9      70  153-155 (dec.) (EtOH)                                                                    3392, 1654, 1576,                                                            1508, 1465, 1381,                                                             1340, 1270, 1192,                                                             1077, 1013, 863, 745,                                                         701                         78*.sup.8                                                                        H                                                                                   ##STR68##         3 9      75  199-202 (dec.) (DMSOH.sub.2                                                             3400, 1663, 1647,                                                             1597, 1510, 1463,                                                             1398, 1380, 1339,                                                             1271, 1225, 1168,                                                             718                         79*.sup.4                                                                        5-NO.sub.2                                                                          ##STR69##         3 9      80  181-183 (MeOHCH.sub.3 CN)                                                               3492, 3400, 1671,                                                             1618, 1593,1513,                                                              1484, 1466, 1384,                                                             1339, 1273, 1229,                                                             1080, 759, 742              80*.sup.1                                                                        3-OCH.sub.3 5-NO.sub.2                                                              ##STR70##         3 9      75  147-150 (dec.) (MeOHH.sub.2                                                             3410, 1662, 1514,                                                             1460, 1374, 1338,                                                             1291, 1236, 1139,                                                             1098, 1060, 1021,                                                             951,                      __________________________________________________________________________                                                        747                        *.sup.1 Dihydrochloride                                                       *.sup.2 Dimaleate                                                             *.sup.3 Fumarate                                                              *.sup.4 Hydrochloride                                                         *.sup.5 Difumarate                                                            *.sup.6 Maleate                                                               *.sup.7 Oxalate                                                               *.sup. 8 Dioxalate                                                       

                                      TABLE V                                     __________________________________________________________________________     ##STR71##                                                                                               Method                                                                        of         mp(°C.)                          Compd.                     prepn. Yield                                                                             (Recrystn.                              No.  R.sup.2                                                                            R.sup.6        r (Examp. No.)                                                                         (%) solvent)  IR(KBr,                       __________________________________________________________________________                                                    cm.sup.-1)                    81*  4-OCH.sub.3                                                                         ##STR72##     4 9      85  168-169 (MeOHCH.sub.3 CN)                                                               3450, 1682, 1620, 1580,                                                       1515, 1460, 1375, 1359,                                                       1336, 1260, 1240, 1139,                                                       1027, 865,                    __________________________________________________________________________                                                    745                            *Dimalate                                                                

                                      TABLE VI                                    __________________________________________________________________________     ##STR73##                                                                                               Method                                                                        of         mp(°C.)                          Compd.                     prepn. Yield                                                                             (Recrystn.                              No.  R.sup.2                                                                            R.sup.6        r (Examp. No.)                                                                         (%) solvent) IR(KBr, cm.sup.-1)             __________________________________________________________________________    82*.sup.1                                                                          H                                                                                   ##STR74##     3 9      60  175-177 (dec.) (MeOHCH.sub.3                                                           3420, 1712, 1660, 1575,                                                       1509, 1462, 1373, 1300,                                                       1260, 1233, 1171, 1024,                                                       970, 757                         83*.sup.2                                                                        3-OCH.sub.3                                                                         ##STR75##     3 9      85  164-165 (MeOHCH.sub.3 CN)                                                              3430, 1665, 1619, 1570,                                                       1510, 1460, 1375, 1353,                                                       1325, 1256, 1235, 1132,                                                       1025, 865                        84*.sup.2                                                                        3-OCH.sub.3                                                                         ##STR76##     4 9      80  167-168 (MeOCH.sub.3 CN)                                                               3430, 1670, 1570, 1450,                                                       1370, 1355, 1325, 1255,                                                       1240, 1130, 1025, 865,                                                        750                              85*.sup.2                                                                        3-OCH.sub.3  5-OCH.sub.3                                                            ##STR77##     4 9      70  163.5-165.5                                                                            3450, 1670, 1577, 1499,                                                       1460, 1379, 1328, 1261,                                                       1236, 1122, 1024,              __________________________________________________________________________                                                   866                             *.sup.1 Difumarate                                                            *.sup.2 Dimaleate                                                        

                                      TABLE VII                                   __________________________________________________________________________     ##STR78##                                                                                     Method                                                                        of         mp(°C.)                                    Comp.            prepn. Yield                                                                             (Recrystn.                                        No. R.sup.4                                                                             R.sup.5                                                                              (Examp. No.)                                                                         (%) solvent)                                                                              IR(KBr, cm.sup.-1)                        __________________________________________________________________________    86* H     C(CH.sub.3).sub.3                                                                    1      81  188-192 3350, 2980, 2790, 1672, 1660,                              2          (CHCl.sub.3Et.sub.2 O)                                                                1470, 1384, 1224, 750                        87a*                                                                           CH.sub.3                                                                             ##STR79##                                                                           1      35  208-210 3225, 2940, 1686, 1464, 1382, 744            87b*                                                                           CH.sub.3                                                                             ##STR80##                                                                           1      30  143-146 3350, 2940, 1672, 1464, 1382, 748           88*                                                                             CH.sub.2 CH.sub.3                                                                   CH.sub.2 CH.sub.3                                                                    1      75  amorph. 3400, 2930, 1658, 1600, 1460,                                                 1380, 1326, 1274, 1234, 1102,                                                 1028, 750                                 __________________________________________________________________________     *Hydrochloride                                                                Compound 87a is the diastereoisomer of compound 87b.                     

                                      TABLE VIII                                  __________________________________________________________________________     ##STR81##                                                                                               Method                                                                        of         mp(°C.)                          Compd.                     prepn. Yield                                                                             (Recrystn.                              No.  R.sup.2                                                                            R.sup.9        r (Examp. No.)                                                                         (%) solvent)  IR(KBr,                       __________________________________________________________________________                                                    cm.sup.-1)                    89*.sup.1                                                                          H                                                                                   ##STR82##     3 5      70  124-127   3430, 2940, 1674, 1466,                                                       1380, 746                       90 H                                                                                   ##STR83##     3 3      55  121-122.5 1676, 1466, 1456, 1374,                                                       1324, 1276, 1252, 1230,                                                       1116, 752                       91*.sup.2                                                                        H                                                                                   ##STR84##     3 9      75  184-186 (dec.)                                                                          3450, 1728, 1685, 1605,                                                       1465, 1384, 1280, 1254,                                                       1238, 758                       92*.sup.2                                                                        5-OCH.sub.3                                                                         ##STR85##     4 9      70  148-150 (iso-PrOH  AcOEt Et.sub.2                                             O)        3420, 1705, 1669, 1493,                                                       1463, 1379, 1320, 1275,                                                       1237, 1207, 1140, 745            93*.sup.3                                                                       5-OCH.sub.3                                                                         ##STR86##     4 9      80  182-184 (MeOHCH.sub.3 CN)                                                               3450, 1720, 1671, 1595,                                                       1461, 1378, 1278, 1208,                                                       702                             94*.sup.3                                                                        5-NO.sub.2                                                                          ##STR87##     3 9      75  175-178 (dec.) (MeOHCH.sub.3                                                            3408, 1664, 1610, 1592,                                                       1509, 1459, 1381, 1340,                                                       1270, 1226, 1074, 744,                                                        700                             95*.sup.3                                                                        5-NO.sub.2                                                                          ##STR88##     4 9      70  190-191 (dec.) (MeOHCH.sub.3                                                            3424, 1718, 1689, 1608,                                                       1594, 1510, 1465, 1376,                                                       1339, 1269, 1195, 744,        __________________________________________________________________________                                                    701                            *.sup.1 Hydrochloride                                                         *.sup.2 Fumarate                                                              *.sup.3 Oxalate                                                          

                                      TABLE IX                                    __________________________________________________________________________                              Method                                                                        of          mp(°C.)                          Compd.                    prepn.  Yield                                                                             (Recrystn.                              No.  R.sup.8            r (Examp. No.)                                                                          (%) solvent)  IR(KBr,                       __________________________________________________________________________                                                    cm.sup.-1)                    96   OH                 3 11      80  121-122.5 3420, 1725, 1636, 1465,                                                       1387,                                                               (AcOEtEt.sub.2 O                                                                        1272, 1242, 1231, 1176,                                                       1100,                                                               Me.sub.2 CHOCHMe.sub.2)                                                                 1040, 745                     97   OCH.sub.2 CH.sub.3 3 10      75  oil       1735, 1679, 1601, 1491,                                                       1468,                                                                         1380, 1325, 1273, 1247,                                                       1230,                                                                         1178, 1100, 1028, 730                                                         (neat)                          98                                                                                ##STR89##         3 12      65  amorph.   3310, 1650, 1510, 1461,                                                       1375, 1321, 1257, 1230,                                                       1023, 745                        99*                                                                              ##STR90##         3 12      80  195.5-197 (dec.)  (EtOHH.sub.2                                                          3430, 1652, 1465, 1376,                                                       1328, 1243, 1159, 1022,                                                       975, 747, 642                   100                                                                               ##STR91##         3 12      75  133-134 (AcOEt)                                                                         1670, 1639, 1599, 1460,                                                       1373, 1325, 1267, 1227,                                                       1100, 1098, 1028,             __________________________________________________________________________                                                    750                            *Fumarate                                                                

      X NMR No.  δ (ppm), J =      Hz      1 DMSOd.sub.6     ##STR92##         OCH.sub.2), 6.60-7.40 (8H, m, C.sub.2H and ArH), 7.70-8.20 (1H, m,     C.sub.4H), 8.00-8.80 (3H, br, NH.sub.2 and HCl)      2 DMSOd.sub.6     ##STR93##      ##STR94##          (1H, m, C.sub.4H), 9.13 (3H, br s, NHand CO.sub.2 H × 2)   3     DMSOd.sub.6      ##STR95##      ##STR96##         9.40 (2H, br, NHand HCl)      4 DMSOd.sub.6     ##STR97##      ##STR98##         (1H, m, C.sub.4H), 9.50-10.53 (2H, br, NHand HCl)   5 DMSOd.sub.6      ##STR99##         OCH.sub.3), 3.74 (3H, s, OCH.sub.3), 4.23 (2H, t, J =      6.0, OCH.sub.2), 6.60-7.50 (11H, m, C.sub.2H and ArH), 7.70-8.10   (1H,     m, C.sub.4H), 9.50 (2H, br s, NHand HCl)      6 DMSOd.sub.6     ##STR100##         6.73-7.63 (8H, m, C.sub.2H and ArH), 7.80-8.23 (1H, m, C.sub.4H),     11.53 (1H, br s, HCl)      7 CDCl.sub.3     ##STR101##         OCH.sub.2 CH.sub.2), 6.60-7.40 (8H, m, C.sub.2H and ArH), 7.70-8.30     (1H, m, C.sub.4H)      8 DMSOd.sub.6     ##STR102##      ##STR103##         (1H, m, C.sub.4H), 10.80-11.50 (1H, br, HCl)   9 DMSOd.sub.6      ##STR104##      ##STR105##      ##STR106##         CO.sub.2 H × 2)      10 DMSOd.sub.6     ##STR107##         6H, m, CH.sub.2 N(CH.sub.2 CH.sub.3).sub.2), 4.22 (2H, t, J = 5.5,     OCH.sub.2), 6.70-7.40 (8H, m, C.sub.2H and ArH), 7.70-8.10   (1H, m,     C.sub.4H), 10.90-11.50 (1H, br, HCl)      11 DMSOd.sub.6     ##STR108##         3.40 (6H, m, CH.sub.2 N(CH.sub.2 CH.sub.3).sub.2), 3.90-4.33 (2H, m, O     CH.sub.2), 6.60-7.57 (8H, m, C.sub.2H and ArH), 7.67-8.23   (1H, m,     C.sub.4H), 10.63-11.40 (1H, br, HCl)      12 DMSOd.sub.6     ##STR109##         3.90-4.50 (2H, m, OCH.sub.2), 6.70-7.50 (8H, m, C.sub.2H) and ArH),     7.70-8.10 (1H, m, C.sub.4H), 10.10-10.60   (1H, br, HCl)  13 DMSOd.sub.6      ##STR110##         (4H, m, CH.sub.2 OH × 2), 4.17 (2H, t, J = 5.5, OCH.sub.2),     4.50-5.20 (2H, br, OH × 2), 6.60-7.50 (8H, m,   C.sub.2H and ArH),     7.70-8.20 (1H, m, C.sub.4H), 10.00-10.60 (1H, br, HCl)  14 DMSOd.sub.6      ##STR111##      ##STR112##         7.40 (6H, m, C.sub.2H and ArH), 7.73-8.16 (1H, m, C.sub.4H),     10.50-11.73 (1H, br, HCl)      15 CDCl.sub.3     ##STR113##      ##STR114##         6.70-7.30 (6H, m, C.sub.2H and ArH), 7.56-8.30 (1H, m, C.sub.4H),     11.87-12.80 (1H, br, HCl)      16 DMSOd.sub.6     ##STR115##      ##STR116##         6.52 (1H, dd, J = 6.0, 3.5, C.sub.4 'H), 6.63- 7.27 (6H, m, C.sub.2H     and ArH), 7.63-8.17 (1H, m, C.sub.4H), 10.00-   14.50 (2H, br, CO.sub.2     H × 2)      17 CDCl.sub.3     ##STR117##      ##STR118##         C.sub.4 'H), 6.57-7.30 (6H, m, C.sub.2H and ArH), 7.57-8.23 (1H, m,     C.sub.4H), 11.40-12.23 (1H, br, HCl)      18 CDCl.sub.3     ##STR119##      ##STR120##         C.sub.6 'H), 6.63-7.30 (6H, m, C.sub.2H and ArH), 7.57-8.30 (1H, m,     C.sub.4H), 12.65-15.50 (2H, br, CO.sub.2 H × 2)  19 DMSOd.sub.6      ##STR121##      ##STR122##         C.sub.6 'H), 6.62-7.37 (6H, m, C.sub.2H and ArH), 7.63-8.20 (1H, m,     C.sub.4H), 9.82 (2H, br s, CO.sub.2 H × 2)   20 DMSOd.sub.6      ##STR123##      ##STR124##         6.62-7.40 (6H, m, C.sub.2H and ArH), 7.70-8.20 (1H, m, C.sub.4H),     9.75 (2H, br s, CO.sub.2 H × 2)      21 DMSOd.sub.6     ##STR125##      ##STR126##      ##STR127##      22 DMSOd.sub.6     ##STR128##      ##STR129##         6.63-7.40 (6H, m, C.sub.2H and ArH), 7.67-8.20 (1H, m, C.sub.4H),     9.17 (2H, br s, CO.sub.2 H × 2)      23 DMSOd.sub.6     ##STR130##      ##STR131##         3.80-4.20 (2H, m, OCH.sub.2), 6.45 (1H, d, J = 2.0, C.sub.6 'H),     6.60-7.30 (9H, C.sub.2H and ArH), 7.70-8.10   (1H, m, C.sub.4H),     10.90-11.50 (1H, br, HCl)      24 DMSOd.sub.6     ##STR132##         3.23 (3H, s, OCH.sub.3 (P)), 3.70-4.00 (2H, m, CH.sub.2 OH),     3.90-4.30 (2H, m, OCH.sub.2), 4.67 (1H, s, OH),   6.41 (1H, d, J = 2.0,     C.sub.6 'H), 6.70-7.30 (6H, m, C.sub.2H and Ar H), 7.70-8.20 (1H, m,     C.sub.4H), 9.90-10.40   (1H, br, HCl)      25 DMSOd.sub.6     ##STR133##         3.57 (3H, s, OCH.sub.3 (P)), 3.65 (3H, s, OCH.sub.3 (A)), 3.71 (3H,     s, OCH.sub.3 (A)), 3.90-4.30 (2H, m, OCH.sub.2),    6.42 (1H, d, J =     2.0, C.sub.6 'H), 6.60-7.20 (9H, m, C.sub.2H and ArH), 7.70-8.20 (1H, m,     C.sub.4H), 10.90-11.30   (1H, br, HCl)      26 DMSOd.sub.6     ##STR134##      ##STR135##         m, C.sub.4H), 11.00-11.90 (1H, br, HCl)      27 CDCl.sub.3     ##STR136##      ##STR137##         m, C.sub.4H), 7.77 (1H, dd, J = 8.0, 2.0, C.sub.4 'H), 11.30-12.20     (1H, br, HCl)      28 DMSOd.sub.6     ##STR138##      ##STR139##         C.sub.7H), 7.28 (1H, d, J = 9.0, C.sub.3 'H), 7.72 (1H, d, J = 3.0,     C.sub.6 'H), 7.83-8.10 (1H, m, C.sub.4H), 8.15 (1H,   dd, J = 9.0, 3.0,     C.sub.4 'H), 11.33 (2H, s, CO.sub.2 H × 2)  29 DMSOd.sub.6      ##STR140##      ##STR141##         C.sub. 2H, C.sub.5H, C.sub.6and C.sub.7H), 7.26 (1H, d, J = 9.0,     C.sub.3 'H), 7.73 (1H, d, J = 2.5, C.sub.6 'H), 7.80-8.10 (1H,    m,     C.sub.4H), 8.17 (1H, dd, J = 9.0, 2.5, C.sub.4 'H), 9.65 (2H, br s,     CO.sub.2 H × 2)      30 DMSOd.sub.6     ##STR142##      ##STR143##         C.sub.5H, C.sub.6H, C.sub.7H and C.sub.3 'H), 7.60-8.20 (1H, m,     C.sub.4H), 7.72 (1H, d, J = 2.5, C.sub.6 'H), 8.15 (1H, dd,   J = 9.0,     2.5, C.sub.4 'H), 9.73-10.52 (2H, br, CO.sub.2 H × 2)      31 DMSOd.sub.6      ##STR144##      ##STR145##         C.sub.2H, C.sub.5H, C.sub.6H, C.sub.7H and C.sub.3 'H), 7.72 (1H, d,     J = 2.5, C.sub.6 'H), 7.62-8.17 (1H, m, C.sub.4H), 8.16 (1H,   dd, J =     9.0, 2.5, C.sub.4 'H), 9.32-10.08 (2H, br, CO.sub.2 H × 2)  32     d     DMSO.sub.6      ##STR146##      ##STR147##         C.sub.5H, C.sub.6H, C.sub.7H and C.sub.3 'H), 7.72 (1H, d, J = 2.5,     C.sub.6 'H), 7.57-8.20 (1H, m, C.sub.4H), 8.18 (1H, dd,    J = 9.0, 2.5,     C.sub.4 'H), 9.43-10.13 (2H, br, CO.sub.2 H × 2)                   d      33 CDCl.sub.3DMSO.sub.6      ##STR148##      ##STR149##         7.48-7.92 (2H, m, C.sub.4H and C.sub.3 'H), 7.78 (1H, d, J = 3.0,     C.sub.6 'H), 8.12 (1H, dd, J = 9.0, 3.0, C.sub.4 'H),      ##STR150##      34 DMSOd.sub.6     ##STR151##      ##STR152##         6.85-7.33 (4H, m, C.sub.2H, C.sub.5H, C.sub.6H and C.sub.7H), 7.38     (1H, d, J = 2.5, C.sub.4 'H), 7.67-8.10 (1H, m, C.sub.4H),   7.78 (1H,     d, J = 2.5, C.sub.6 'H), 11.05 (2H, br s, CO.sub.2 H × 2)  35     DMSOd.sub.6      ##STR153##      ##STR154##         7.70-8.10 (1H, m, C.sub.4H), 11.44 (2H, s, CO.sub.2 H × 2)  36     CDCl.sub.3      ##STR155##      ##STR156##      37 DMSOd.sub.6     ##STR157##      ##STR158##         7.70-8.10 (1H, m, C.sub.4H), 10.00-11.37 (3H, br, CO.sub.2 H ×     2 and OH)      38 DMSOd.sub.6     ##STR159##      ##STR160##         and ArH), 7.73-8.10 (1H, m, C.sub.4H), 10.47-11.07 (1H, br, HCl)  39     DMSOd.sub.6      ##STR161##      ##STR162##         8.10 (1H, m, C.sub.4H), 7.78 (1H, d, J = 9.0, C.sub.5      'H), 10.71-11.32 (1H, br, HCl)      40 CDCl.sub.3DMSOd.sub.6     ##STR163##      ##STR164##         8.10 (1H, m, C.sub.4H), 8.23 (1H, d, J = 9.0, C.sub.3      'H), 11.30-12.00 (1H, br, HCl)      41 DMSOd.sub.6     ##STR165##         J = 5.0, OCH.sub.2), 6.90-7.40 (4H, m, C.sub.2H, C.sub.5H, C.sub.6H     and C.sub.7H), 6.95 (2H, d, J = 9.0, C.sub.3 'H and C.sub.5 'H),   7.23     (2H, d, J = 9.0, C.sub.2 'H and C.sub.6      'H), 7.80-8.10 (1H, m, C.sub.4H), 10.90-11.70 (1H, br, HCl)  42     DMSOd.sub.6      ##STR166##      ##STR167##         6.80 (2H, d, J = 9.0, C.sub.3 'H and C.sub.5 'H), 7.12 (2H, d, J =     9.0, C.sub.2 'H and C.sub.6      'H), 7.60-8.00 (1H, m, C.sub.4H),   11.00-11.60 (1H, br, HCl)  43     DMSOd.sub.6      ##STR168##      ##STR169##         6.82 (2H, d, J = 8.5, C.sub.3 'H and C.sub.5 'H), 7.29 (2H, d, J =     8.5, C.sub.2 'H and C.sub.6      'H), 7.70-8.10 (1H, m, C.sub.4H),   10.80-11.50 (1H, br, HCl)  44     DMSOd.sub.6      ##STR170##      ##STR171##         6.81 (2H, d, J = 9.0, C.sub.3 'H and C.sub.5 'H), 7.15 (2H, d, J =     9.0, C.sub.2 'H and C.sub.6      'H), 7.70-8.00 (1H, m, C.sub.4H),   10.70-11.30 (1H, br, HCl)  45     DMSOd.sub.6      ##STR172##      ##STR173##         7.30 (4H, m, C.sub.2H, C.sub.5H, C.sub.6H and C.sub.7H), 7.21 (2H,     d, J = 8.5, C.sub.2 'H and C.sub.6 'H), 7.70-8.10 (1H, m,   C.sub.4H),     10.50-11.20 (1H, br, HCl)      46 DMSOd.sub.6     ##STR174##         (6H, m, CH.sub.2 N(CH.sub.2 CH.sub.3).sub.2), 4.03 (2H, t, J = 6.0,     OCH.sub.2), 6.80-7.40 (4H, m, C.sub.2H, C.sub.5H, C.sub.6H and C.sub.7H),        6.83 (2H, d, J = 8.5, C.sub.3 'H and C.sub.5 'H), 7.16 (2H, d, J =     8.5, C.sub.2 'H and C.sub.6      'H), 7.70-8.00 (1H, m, C.sub.4H),   10.70-11.30 (1H, br, HCl)  47     CDCl.sub.3      ##STR175##      ##STR176##         C.sub.2H and ArH), 7.57-8.10 (1H, m, C.sub.4H), 8.83-9.30 (1H, br,     OH)      48 DMSOd.sub.6     ##STR177##      ##STR178##         7.70-8.10 (1H, m, C.sub.4H), 10.77-11.50 (1H, br, HCl)      49 DMSOd.sub.6      ##STR179##      ##STR180##         7.70-8.10 (1H, m, C.sub.4H), 10.53-11.37 (1H, br, HCl)      50 DMSOd.sub.6      ##STR181##      ##STR182##         ArH), 7.70-8.13 (1H, m, C.sub.4H), 10.67-11.33 (1H, br, HCl)  51     d     DMSO.sub.6      ##STR183##      ##STR184##         C.sub.2H and ArH), 7.73-8.10 (1H, m, C.sub.4H), 10.50-11.07 (1H, br,     HCl)      52 DMSOd.sub.6     ##STR185##      ##STR186##         (1H, m, C.sub.4H), 7.33 (1H, dd, J = 9.0, 2.5, C.sub.6 'H), 7.78     (1H, d, J = 2.5, C.sub.2 'H), 11.17-11.85 (1H, br, HCl)  53 DMSOd.sub.6      ##STR187##      ##STR188##         6.98 (1H, s, C.sub.2H), 6.93-7.33 (3H, m, C.sub.5H, C.sub.6H and     C.sub.7H), 7.80-8.00 (1H, m, C.sub.4H), 10.90-11.40   (1H, br, HCl)  54     DMSOd.sub.6      ##STR189##      ##STR190##         and C.sub.6 'H), 7.01 (1H, s, C.sub.2H), 7.00-7.40 (3H, m, C.sub.5H,     C.sub.6H and C.sub.7H), 7.77-8.10 (1H, m, C.sub.4H),   10.68-11.20 (1H,     br, HCl)      55 DMSOd.sub.6     ##STR191##      ##STR192##         C.sub.6 'H), 7.00-7.50 (4H, m, C.sub.2H, C.sub.5H, C.sub.6H and     C.sub.7H), 7.80-8.10 (1H, m, C.sub.4H), 10.70-11.20 (1H, br, HCl)  56     DMSOd.sub.6      ##STR193##      ##STR194##         C.sub.4H), 11.20-12.50 (2H, br, HCl × 2)  57 DMSOd.sub.6      ##STR195##      ##STR196##         11.77-13.03 (4H, br, CO.sub.2 H × 4)      58 DMSOd.sub.6     ##STR197##         3.73 (3H, s, OCH.sub.3 (A)), 3.77 (3H, s, OCH.sub.3 (A)), 4.17 (2H,     br t, J = 5.0, OCH.sub.2), 6.13 (4H, s,      ##STR198##         CO.sub.2 H × 4)      59 DMSOd.sub.6     ##STR199##      ##STR200##      ##STR201##      60 DMSOd.sub.6     ##STR202##      ##STR203##         and ArH), 7.67-8.20 (1H, m, C.sub.4H), 10.87 (2H, br s, CO.sub.2 H     × 2)      61 DMSOd.sub.6     ##STR204##         3.78 (3H, s, OCH.sub.3 (A)), 3.82 (3H, s, OCH.sub.3 (A)), 4.20 (2H,     t, J = 6.0, OCH.sub.2), 6.62-7.70 (13H, m,      ##STR205##      62 DMSOd.sub.6     ##STR206##         3.57 (3H, s, OCH.sub.3 (P)), 3.70 (3H, s, OCH.sub.3 (A)), 3.73 (3H,     s, OCH.sub.3 (A)), 4.10 (2H, br t, J = 5.0,      ##STR207##         7.68-8.20 (1H, m, C.sub.4H), 11.37-12.83 (4H, br, CO.sub.2 H ×     4)      63 DMSOd.sub.6     ##STR208##         3.55 (3H, s, OCH.sub.3 (P)), 3.67 (3H, s, OCH.sub.3 (A)), 3.70 (3H,     s, OCH.sub.3 (A)), 3.87-4.32 (2H, m, OCH.sub.2),      ##STR209##         (1H, m, C.sub.4H), 10.83 (4H, br s, CO.sub.2 H × 4)  64     DMSOd.sub.6      ##STR210##         3.59 (3H, s, OCH.sub.3 (P)), 3.70 (3H, s, OCH.sub.3 (A)), 3.74 (3H,     s, OCH.sub.3 (A)), 3.80-4.30 (2H, m, OCH.sub.2),      ##STR211##         (1H, m, C.sub.4H), 10.90-12.20 (4H, br, CO.sub.2 H × 4)  65     DMSOd.sub.6      ##STR212##         3.57 (3H, s, OCH.sub.3 (P)), 3.70 (3H, s, OCH.sub.3 (A)), 3.73 (3H,     s, OCH.sub.3 (A)), 3.87-4.33 (2H, m, OCH.sub.2),      ##STR213##         m, C.sub.4H), 11.17-12.67 (4H, br, CO.sub.2 H × 4)  66     DMSOd.sub.6      ##STR214##         3.53 (3H, s, OCH.sub.3 (P)), 3.65 (2H, t, J = 5.5, CH.sub.2 OH),     3.87-4.23 (2H, m, OCH.sub.2), 6.12 (4H, s,      ##STR215##         9.20-11.20 (5H, br, CO.sub.2 H × 4 and OH)  67 DMSOd.sub.6      ##STR216##         3.59 (3H, s, OCH.sub.3 (P)), 3.64 (3H, s, OCH.sub.3 (A)), 3.78 (6H,     s, OCH.sub.3 × 2 (A)), 3.84-4.30 (2H, m,      ##STR217##         7.80-8.10 (1H, m, C.sub.4H), 11.00-13.50 (2H, br, HCl × 2)  68     DMSOd.sub.6      ##STR218##         3.56 (3H, s, OCH.sub.3 (P)), 3.74 (3H, s, OCH.sub.3 (A)), 3.77 (3H,     s, OCH.sub.3 (A)), 3.79 (3H, s, OCH.sub.3 (A)),      ##STR219##      ##STR220##      ##STR221##      69 DMSOd.sub.6     ##STR222##      ##STR223##      ##STR224##         br s, CO.sub.2 H × 4)      70 DMSOd.sub.6     ##STR225##         3.59 (3H, s, OCH.sub.3 (P)), 3.74 (3H, s, OCH.sub.3 (A)), 3.82 (6H,     s, OCH.sub.3 × 2 (A)), 3.93-4.23 (2H, m,      ##STR226##         7.37 (6H, m, C.sub.2H and ArH), 7.67-8.13 (1H, m, C.sub.4H),     9.50-11.50 (4H, br, CO.sub.2 H × 4)      71 DMSOd.sub.6     ##STR227##         (3H, s, OCH.sub.3 (P)), 3.70 (6H, s, OCH.sub.3 × 2 (A)), 4.03     (2H, t, J = 5.0, OCH.sub.2), 6.45 (1H, d, J = 2.0,      ##STR228##         br s, CO.sub.2 H × 2)      72 DMSOd.sub.6     ##STR229##      ##STR230##      ##STR231##         7.70-8.10 (1H, m, C.sub.4H), 9.83-12.00 (2H, br, CO.sub.2 H ×     2)      73 DMSOd.sub.6     ##STR232##      ##STR233##         m, C.sub.2H, C.sub.5H, C.sub.6H, C.sub.7H and C.sub.3 'H), 7.75 (1H,     d, J = 2.5, C.sub.6 'H), 7.70-8.37 (1H, m, C.sub.4H), 8.23 (1H,   dd, J     = 9.0, 2.5, C.sub.4 'H), 11.30-12.50 (4H, br, CO.sub.2 H × 4)  74     DMSOd.sub.6      ##STR234##      ##STR235##      ##STR236##         7.72 (1H, d, J = 2.5, C.sub.6 'H), 7.77-8.10 (1H, m, C.sub.4H), 8.17     (1H, dd, J = 9.0, 2.5, C.sub.4 'H), 11.00-12.27   (4H, br, CO.sub.2 H     × 4)      75 DMSOd.sub.6     ##STR237##      ##STR238##         6.75-7.48 (5H, m, C.sub.2H, C.sub.5 H, C.sub.6H, C.sub.7H and     C.sub.3 'H), 7.63 (1H, d, J = 2.5, C.sub.6 'H), 7.65-8.25 (2H, m,     C.sub.4H and C.sub.4 'H), 10.38 (2H, br s, CO.sub.2 H × 2)  76     d     DMSO.sub.6      ##STR239##      ##STR240##         8.19 (1H, d, J = 9.0, 2.5, C.sub.4 'H), 10.50-11.92 (4H, br,     CO.sub.2 H × 4)      77 DMSOd.sub.6     ##STR241##      ##STR242##         6.80-7.42 (5H, m, C.sub.2H, C.sub.5H, C.sub.6H, C.sub.7H and C.sub.3     'H), 7.28 (5H, s, C.sub.6 H.sub.5), 7.62-8.32 (1H, m, C.sub.4H),   7.69     (1H, d, J = 2.5, C.sub.6 'H), 8.14 (1H, dd, J = 9.0, 2.5, C.sub.4 'H),     9.00-11.75 (5H, br, CO.sub.2 H × 4 and OH)  78 DMSOd.sub.6      ##STR243##      ##STR244##         m, C.sub.2H, C.sub.5H, C.sub.6H, C.sub.7H and C.sub.3 'H), 7.67-8.51     (3H, m, C.sub.4H, C.sub.4 'H and C.sub.6 'H), 7.88 (2H, d, J = 8.8,      ##STR245##      79 DMSOd.sub.6     ##STR246##      ##STR247##      ##STR248##         C.sub.4 'H), 11.64-12.51 (1H, br, HCl)      80 CDCl.sub.3     ##STR249##         3.81 (3H, s, OCH.sub.3 (A)), 3.84 (3H, s, OCH.sub.3 (A)), 3.90 (3H,     s, OCH.sub.3 (P)), 4.20-4.65 (2H, m, OCH.sub.2),      ##STR250##         and HCl × 2), 7.50 (1H, d, J = 2.5, C.sub.4 'H), 7.67 (1H, d,     J = 2.5, C.sub.6 'H)      81 DMSOd.sub.6     ##STR251##         3.70 (6H, s, OCH.sub.3 × 2 (P, A)), 3.73 (3H, s, OCH.sub.3     (A)), 3.73-4.07 (2H, m, OCH.sub.2), 6.13 (4H, s,      ##STR252##         CO.sub.2 H × 4)      82 DMSOd.sub.6     ##STR253##      ##STR254##         6.63-7.32 (11H, m, C.sub.2H and ArH), 7.69-8.10 (1H, m, C.sub.4H),     11.42 (4H, s, CO.sub.2 H × 4)      83 DMSOd.sub.6     ##STR255##         3.67 (6H, s, OCH.sub.3 × 2 (P, A)), 3.70 (3H, s, OCH.sub.3     (A)), 3.93 (2H, t, J = 6.0, OCH.sub.2), 6.10 (4H, s,      ##STR256##      84 DMSOd.sub.6     ##STR257##         3.70 (6H, s, OCH.sub.3 × 2 (P,A)), 3.73 (3H, s, OCH.sub.3     (A)), 3.97 (2H, t, J = 6.0, OCH.sub.2), 6.12 (4H, s,      ##STR258##      85 DMSOd.sub.6     ##STR259##         3.63 (6H, s, OCH.sub.3 × 2 (P)), 3.70 (3H, s, OCH.sub.3 (A)),     3.70-4.10 (2H, m, OCH.sub.2), 3.73 (3H, s, OCH.sub.3 (A)),      ##STR260##         (1H, m, C.sub.4H), 10.50-12.00 (4H, br, CO.sub.2 H × 4)  86     CDCl.sub.3      ##STR261##      ##STR262##         7.50-8.50 (1H, m, C.sub.4H), 8.00-10.00 (2H, br, NHand HCl)   87a     DMSOd.sub.6      ##STR263##      ##STR264##         7.50 (8H, m, C.sub.2H and ArH), 7.80-8.20 (1H, m, C.sub.4H),     9.90-11.00 (1H, br, HCl)      87b DMSOd.sub.6     ##STR265##      ##STR266##         ArH), 7.70-8.27 (1H, m, C.sub.4H), 9.70-10.80 (1H, br, HCl) 88     CDCl.sub.3 1.43 (6H, t, J = 7.0, N(CH.sub.2 CH.sub.3).sub.2), 2.32 (3H,     s, COCH.sub.3), 3.10-3.70 (6H, m, CH.sub.2 N(CH.sub.2 CH.sub.3).sub.2),     3.9-4.7   (2H, m, OCH.sub.2 CH), 4.50-5.00 (1H, br, CH(OH)), 5.50-6.10     (1H, br, OH), 6.60-7.40 (8H, m, C.sub.2H   and ArH), 7.50-8.30 (1H, m,     C.sub.4H), 10.50-11.40 (1H, br, HCl)      89 DMSOd.sub.6     ##STR267##      ##STR268##         (1H, m, C.sub.4H), 10.90-11.50 (1H, br, HCl)  90 DMSOd.sub.6      ##STR269##      ##STR270##         C.sub.4H)      91 DMSOd.sub.6     ##STR271##      ##STR272##         (1H, m, C.sub.4H), 10.37 (2H, br s, CO.sub.2 H × 2)  92     DMSOd.sub.6      ##STR273##      ##STR274##         6.80-7.50 (11H, m, C.sub.2H and ArH), 7.80-8.20 (1H, m, C.sub.4H),     9.20-9.83 (2H, br, CO.sub.2 H × 2)      93 CDCl.sub.3     ##STR275##         3.58 (3H, s, OCH.sub.3 (P)), 3.85-4.50 (2H, m, OCH.sub.2), 6.43 (1H,     d, J = 2.0, C.sub.6 'H), 6.67-8.12 (12H, m,   C.sub.2H and ArH), 8.13     (2H, br s, CO.sub.2 H × 2)       94 DMSOd.sub.6     ##STR276##         4.06 (1H, m, CHOH), 4.10-4.69 (2H, m, OCH.sub.2), 6.86-7.60 (5H, m,     C.sub.2H, C.sub.5H, C.sub.6H, C.sub.7H and C.sub.3 'H),   7.71 (1H, d, J     = 2.5, C.sub.6 'H), 7.83-8.49 (1H, m, C.sub.4H), 8.13 (1H, dd, J = 9.0,     2.5, C.sub.4 'H), 8.18 (3H, s,   CO.sub.2 H × 2 and OH)  95     DMSOd.sub.6      ##STR277##         4.61 (2H, m, OCH.sub.2), 6.89-7.55 (10H, m, C.sub.2H and ArH), 7.70     (1H, d, J = 2.5, C.sub.6 'H), 7.81-8.31 (1H,   m, C.sub.4H), 8.28 (1H,     dd, J = 9.0, 2.5, C.sub.4 'H), 9.48 (2H, br s, CO.sub.2 H × 2) 96     CDCl.sub.3 1.88-2.85 (4H, m, OCH.sub.2 CH.sub.2 CH.sub.2 CO.sub.2 H),     2.20 (3H, s, COCH.sub.3), 4.10 (2H, t, J = 5.5, OCH.sub.2), 6.60-7.50     (8H, m, C.sub.2H and ArH), 7.70-8.50 (1H, m, C.sub.4H), 10.88 (1H, br s, C     O.sub.2 H) 97 CDCl.sub.3 1.27 (3H, t, J = 7.0, CO.sub.2 CH.sub.2     CH.sub.3), 1.88-2.80 (4H, m, OCH.sub.2 CH.sub.2 CH.sub.2 CO.sub.2), 2.20     (3H, s, COCH.sub.3), 4.12   (2H, t, J = 6.0, OCH.sub.2), 4.18 (2H, q, J     = 7.0, CO.sub.2 CH.sub.2 CH.sub.3), 6.60-7.40 (8H, m, C.sub.2H and ArH),     7.80-8.50   (1H, m, C.sub.4H)      98 CDCl.sub.3     ##STR278##         (2H, q, J = 7.0, NHCH.sub.2 CH.sub.2), 3.77 (3H, s, OCH.sub.3 (A)),     3.82 (3H, s, OCH.sub.3 (A)), 4.08 (2H, t, J = 5.5,   OCH.sub.2),     5.70-6.20 (1H, br, NH), 6.50-7.50 (11H, m, C.sub.2H and ArH), 7.60-8.50     (1H, m, C.sub.4H)      99 DMSOd.sub.6     ##STR279##      ##STR280##         ArH), 7.80-8.20 (1H, m, C.sub.4H), 10.70 (2H, br s, CO.sub.2 H     × 2)  100       CDCl.sub.3     ##STR281##         t, J = 5.5, OCH.sub.2), 6.60-7.40 (8H, m, C.sub.2H and ArH),     7.70-8.50 (1H, m, C.sub.4H)

Pharmacological Activities

Calcium antagonists have not only potentially beneficial effects in thetreatment of many diseases but also serve as valuable research tools toelucidate excitation-contraction coupling in various muscle types (A.Fleckenstein, Ann. Rev. Pharmacol., 17, 149-166, 1977). Therefore, weexamined the calcium-antagonistic activity of the compounds of thisinvention.

Pharmacological test I

The action potentials on the smooth muscles of uterus, teania coli andportal vein are dependent on calcium ion, and therefor these smoothmuscle preparations are useful for screening of calcium antagonists. Wemeasured the calcium-antagonistic activity of the compounds by themethod using guinea-pig teania coli preparation.

Isolated guinea-pig teania coli was suspended in a 20 ml organ bath withKrebs solution at 32° C. and bubbled with 5% carbon dioxide in oxygen.After equilibration, the muscle was washed with Ca⁺⁺ -free Krebssolution, and when the muscle had relaxed to basal level, it wassuspended in Ca⁺⁺ -free-high-K Krebs solution.

The muscle was exposed to test compounds for 5 minutes before additionof CaCl₂, and the contraction evoked by CaCl₂ (3×10⁻⁴ M) was recordedisotonically. The calcium-antagonistic activity was represented by theconcentration of test compound which elicited 50% inhibition of Ca⁺⁺-evoked contraction (IC₅₀).

As shown in Table XI, the compounds of this invention hadcalcium-antagonistic activity.

Blood platelet plays an important role only in hemostasis but also inthrombosis. Platelet hyperaggregability leads to an inclease in thenumber of circulating platelet aggregates, which may contribute towardthe development of cardiac arrythmias, cardiac arrest or myocardialinfarction. These cardiovascular diseases can be prevented by inhibitionof platelet aggregation. Therefor, we screened the influence of testcompounds on platelet aggragation in vitro, and found that they haveanti-aggregatory activity.

Pharmacological test II

Blood was obtained from an anesthetized rabbit using 0.1 volumes of 3.8%sodium citrate as anticoagulant. Platelet rich plasma (PRP) was isolatedby centrifugation at 650 rpm for 10 minutes at room temperature. Afterpreincubation of PRP (0.25 ml) with various concentrations of testcompounds (14 μl) for 1 minute at 37° C., collagen (3 μg/ml: finalconcentration) or ADP (3 μM: final concentration) was added to induceaggregation and the aggregation profiles were monitored with RIKADENKIsix-channel aggregometer. The control experiment contained salineinstead of test compound.

The anti-aggregatory activity was represented by the concentration oftest compound which elicited 50% inhibition of control response.

As shown in the Table XII, the compounds of this invention hadanti-aggregatory activity.

                  TABLE XI                                                        ______________________________________                                        Calcium-antagonistic activity                                                 Compound No.    IC.sub.50 [M]                                                 ______________________________________                                        23              6.6 × 10.sup.-7                                         33              5.2 × 10.sup.-7                                         63              6.4 × 10.sup.-7                                         67              4.7 × 10.sup.-7                                         ______________________________________                                    

                  TABLE XII                                                       ______________________________________                                        Anti-aggregatory activity                                                     Compound No.    IC.sub.50 [M]                                                 ______________________________________                                         8              4.6 × 10.sup.-6                                         21              1.3 × 10.sup.-6                                         22              1.1 × 10.sup.-6                                         29              3.2 × 10.sup.-6                                         54              3.1 × 10.sup.-6                                         55              2.0 × 10.sup.-6                                         95              2.7 × 10.sup.-6                                         ______________________________________                                    

Toxicity test

Acute toxicity of the compounds of this invention is shown in TableXIII. (animal)

Male ddy-SLC strain rats (4 weeks of age, weighing 19-21 g) were placedin a breeding room of constant temperature and huminity (23±1° C.,55±5%) and fed freely pellet diet and water ad. libitum for a week. Ratsshowing normal growth were selected for the test. (method ofadministration)

Test compounds are suspended in 0.5% tragacanth suspention andadministered orally in a dose of 0.5 ml/20 g body weight.

                  TABLE XIII                                                      ______________________________________                                        Compound No.   LD.sub.50 (mg/Kg)                                              ______________________________________                                        29             >2,000                                                         63             ≧3,000                                                  67             >1,000                                                         ______________________________________                                    

The compounds can be administered either orally or parenterally. Thedosage forms are tablet, capsule, granule, powder, suppository,injection, etc. The dose is adjusted depending on symptom, dosage form,etc., but usual daily dosage is 1 to 5,000 mg, preferably 10 to 1,000mg, in one or a few divided doses.

Examples of formulation are shown below.

    ______________________________________                                        Example of formulation                                                        ______________________________________                                        (a)   tablet                                                                        compound 8             30     mg                                              lactose                150    mg                                              crystalline cellulose  50     mg                                              calcium carboxymethylcellulose                                                                       7      mg                                              magnesium stearate     3      mg                                              total                  240    mg                                              compound 21            50     mg                                              lactose                120    mg                                              crystalline cellulose  60     mg                                              calcium carboxymethylcellulose                                                                       7      mg                                              magnesium stearate     3      mg                                              total                  240    mg                                              compound 22            60     mg                                              lactose                120    mg                                              crystalline cellulose  60     mg                                              calcium carboxymethylcellulose                                                                       7      mg                                              magnesium stearate     3      mg                                              total                  250    mg                                              compound 23            40     mg                                              lactose                150    mg                                              crystalline cellulose  50     mg                                              calcium carboxymethylcellulose                                                                       7      mg                                              magnesium stearate     3      mg                                              total                  250    mg                                              compound 33            70     mg                                              lactose                110    mg                                              crystalline cellulose  60     mg                                              calcium carboxymethylcellulose                                                                       7      mg                                              magnesium stearate     3      mg                                              total                  250    mg                                        ______________________________________                                    

The tablets may be treated with the common film-coating and further withsugar-coating.

    ______________________________________                                        (b)     granule                                                                       compound 63        30     mg                                                  polyvinylpyrrolidone                                                                             25     mg                                                  lactose            385    mg                                                  hydroxypropylcellulose                                                                           50     mg                                                  talc               10     mg                                                  total              500    mg                                                  compound 29        50     mg                                                  polyvinylpyrrolidone                                                                             25     mg                                                  lactose            365    mg                                                  hydroxypropylcellulose                                                                           50     mg                                                  talc               10     mg                                                  total              500    mg                                          (c)     powder                                                                        compound 54        30     mg                                                  lactose            500    mg                                                  starch             440    mg                                                  colloidal silica   30     mg                                                  total              1000   mg                                                  compound 67        50     mg                                                  lactose            480    mg                                                  starch             440    mg                                                  colloidal silica   30     mg                                                  total              1000   mg                                          (d)     capsule                                                                       compound 55        30     mg                                                  lactose            102    mg                                                  crystalline cellulose                                                                            56     mg                                                  colloidal silica   2      mg                                                  total              190    mg                                                  compound 95        50     mg                                                  glycerol           329.8  mg                                                  butyl p-hydroxybenzoate                                                                          0.02   mg                                                  total              380    mg                                          ______________________________________                                    

UTILITY IN AN INDUSTRIAL FIELD

This invention offers novel compounds which are useful for therapeuticagent.

What we claim is:
 1. A compound of the formula (I) and salts thereof,##STR282## wherein R¹ is lower alkanoyl;R² is one or more group(s)selected from hydrogen, lower alkyl, lower alkoxy, hydroxy, halogen,nitro, halogeno-lower alkyl and sulfamoyl; R³ is ##STR283## R⁶ ishydrogen, alkyl containing 1 to 8 carbon atoms, alkanoyl containing 2 to8 carbon atoms, alkenoyl containing 2 to 8 carbon atoms orfurylcarbonyl, each of which alkyl, alkanoyl and alkenoyl may besubstituted by one or more groups selected from hydroxy, phenyl, andphenylcarbonyloxy, and said phenyl nucleus may be resubstituted by oneor more groups selected from lower alkyl, hydroxy, halogen, loweralkoxy, nitro, cyano, acetamino and lower-alkylamino; R⁷ is hydrogen,hydroxy, phenyl-lower alkyl or benzoyl; Z is straight or branchedalkylene containing 1 to 6 carbon atoms; m is 0 or 1; n is 0 or 1;p is5,wherein the terms lower alkyl, lower alkoxy and lower alkanoyl referto groups having 1 to 6 carbon atoms.
 2. A compound as in claim 1wherein m is
 0. 3. A compound as in claim 1 wherein m is 1, n is 1 and Zis --CH₂ --.
 4. A compound as in claim 1 wherein R¹ is acetyl.
 5. Acompound as in claim 1 wherein R² is hydrogen.
 6. A compound as in claim2 wherein R² is methoxy or nitro.
 7. A compound as in claim 2 wherein R⁷is benzyl and p is
 5. 8. A compound as in claim 2 wherein R⁶ is2-(3,4-dimethoxyphenyl)ethyl or 2-(3,4,5-trimethoxyphenyl)ethyl. 9.3-Acetyl-2-[2-[3-(4-benzylpiperidyl)propoxy]-5-nitrophenyl]-benzothiazolineas in claim
 1. 10.3-Acetyl-2-[2-[4-[4-[2-(3,4-dimethoxyphenyl)ethyl]piperazinyl]-butoxy]-5-methoxyphenyl]benzothiazolineas in claim
 1. 11.3-Acetyl-2-[2-[4-[4-[2-(3,4,5-trimethoxyphenyl)ethyl]-piperazinyl]butoxy]-5-methoxyphenyl]benzothiazolineas in claim
 1. 12. A pharmaceutical composition comprising (i) acompound as in claim 1 in an amount sufficient for treatment for anginacordis, arrhythmia and thrombosis and (ii) at least one pharmaceuticallyacceptable excipient.
 13. A method of treatment for angina cordis,arrhythmia and thrombosis which comprises administering a compositioncomprising a compound as in claim 1 and at least one pharmaceuticallyacceptable excipient. 14.3-Acetyl-2-((2-(3-(4-benzoylmethylpiperazinyl)propoxy)-5-nitrophenyl)-benzothiazoline.